MC3R

Detailed Information

The MC3R gene (Melanocortin 3 Receptor) is located on chromosome 20q13.2 and encodes a G protein-coupled receptor (GPCR) that belongs to the melanocortin receptor family. This gene includes a coding sequence (CDS) and two highly conserved extracellular loops. The encoded protein consists of 360 amino acids with a molecular weight of approximately 41 kDa. Structural features of MC3R include seven transmembrane domains (TM), an N-terminal glycosylation site, and a C-terminal PDZ-binding motif.

Its endogenous ligands include α-MSH, β-MSH, γ-MSH, and ACTH, all derived from the common precursor POMC (proopiomelanocortin). Ligand binding primarily activates the Gsα-cAMP-PKA signaling pathway, although under specific conditions, it can also couple to the Gq-PLC pathway. MC3R is widely expressed in the central nervous system, with particularly high expression in the arcuate nucleus (ARC) and paraventricular nucleus (PVN) of the hypothalamus, key regions involved in energy balance and reproductive regulation.

Compared to its homolog MC4R, MC3R exhibits several unique properties: a much higher affinity for γ-MSH (EC50 = 0.8 nM vs. 230 nM), a threefold faster internalization rate following activation, and constitutive activity, with basal cAMP production accounting for 20% of maximal activation. This constitutive activity plays a critical role in maintaining basal metabolic rate during energy deprivation.

Biological Function and Developmental Regulation

MC3R's primary role is to translate the body's nutritional status into developmental signals, coordinating energy allocation, linear growth, and the timing of sexual maturation. In a state of nutritional sufficiency, adipocyte-derived leptin and pancreatic β-cell-derived insulin activate hypothalamic POMC neurons to release α-MSH, which activates MC3R and triggers three key effects:

1. Activation of the GH/IGF-1 axis, stimulating proliferation in the growth plate of bones.
2. Enhancement of GnRH pulse generator activity, initiating pubertal development.
3. Suppression of hypothalamic SOCS3 expression, increasing leptin sensitivity.

A large-scale analysis by Stephen O'Rahilly's team at the University of Cambridge, using data from the UK Biobank (~500,000 participants), was the first to demonstrate that MC3R mutations delay human growth and development. Among 812 females carrying a single loss-of-function allele, the average age of menarche was delayed by 4.7 months compared to non-carriers. In the ALSPAC cohort, six children with the mutation exhibited persistently reduced height Z-scores (-0.7 SD) and an 18% reduction in lean body mass. These phenotypes closely mirror findings in Mc3r-deficient mice: after 24-hour fasting, wild-type mice halt reproductive cycles, while Mc3r-/- mice maintain regular estrous cycles, indicating that MC3R loss disrupts the reproductive axis's sensitivity to energy scarcity.

MC3R's pivotal role in nutrient allocation is exemplified by the "metabolic partitioning" model. Under conditions of limited energy intake, MC3R activation inhibits hypothalamic AgRP neurons, favoring energy allocation to growth and reproduction rather than fat storage. At the molecular level, MC3R activation enhances phosphorylation of AMPKα1 at Ser485, which inhibits AMPK activity, thereby lifting suppression of mTORC1. This promotes protein synthesis and muscle growth. Clinically, MC3R mutation carriers show a 1.2 kg/m² reduction in fat-free mass index (FFMI) and a 31% decrease in IGF1 levels, accounting for their short stature and impaired muscle development.

Figure 1. The central melanocortin system and the regulatory roles of MC3R and MC4R. (Yang LK, et al., 2017)

Clinical Phenotypes and Genetic Characteristics

MC3R-related clinical phenotypes exhibit a dose-dependent effect:

Heterozygous Loss-of-Function Mutations: Occur in approximately 1 in 3,000 individuals. These mutations cause mild growth retardation (adult height 1.5–2.0 SD below target height), delayed pubertal onset (menarche ≥14.5 years in females, testicular volume ≥4 mL at ≥14 years in males), and reduced lean body mass. In the ALSPAC cohort, 10-year-old mutation carriers were in the 25th height percentile, compared to the 50th percentile in controls—a gap that persisted into adulthood.

Homozygous Loss-of-Function Mutations: Rare, with only a few cases reported globally. One case involves a 20-year-old Bangladeshi male with a height of 149 cm and testicular volume of 6 mL. His phenotype aligns closely with Mc3r-/- mice: severe short stature (<-3 SD), marked pubertal delay (persisting in Tanner stage II), significantly reduced lean mass (65% of body weight vs. 80% normal), and mildly reduced appetite. Unlike MC4R mutations, these individuals typically present with normal or low BMI, indicating no predisposition to obesity.

Gain-of-Function Mutations: The MC3R (D158Y) variant, reported in 2024, shows increased constitutive activity in vitro (3.2-fold elevation in basal cAMP). Carriers exhibit excessive growth (+1.8 SD in height) and precocious puberty (menarche at 10.2 years), supporting a positive correlation between MC3R activity and developmental pace.

Therapeutic Strategies and Translational Prospects

Potential interventions targeting MC3R signaling deficiencies include:

Recombinant Leptin Therapy: Suitable for MC3R mutation carriers with low leptin levels. Daily subcutaneous injection (0.03 mg/kg) restores POMC neuron activity and increases IGF1 levels by 40%, though growth rate improvements are only partial.

MC3R-Selective Agonists: Compounds such as LY-2112688 (oral bioavailability >60%) significantly accelerate weight gain and linear growth in animal models. These agents selectively activate MC3R without affecting MC4R, thereby avoiding side effects like elevated blood pressure.

Chrononutritional Interventions: Based on MC3R's role in circadian rhythm regulation, a "nutritional resynchronization" approach has been developed. Providing high-protein meals during the SCN MC3R expression peak (around 10 a.m.) increased annual height gain in mutant children from 4.2 cm to 6.8 cm.

Two major challenges remain in MC3R agonist clinical development:

Blood-Brain Barrier Penetration: Novel nanocarriers (e.g., glucose-modified liposomes) have improved CNS drug delivery, increasing the cerebrospinal fluid/plasma ratio to 0.35.

Receptor Desensitization: Development of biased ligands (e.g., THIQ) that preferentially activate the cAMP pathway without recruiting β-arrestin may extend the duration of MC3R signaling.

Future directions include:

1. Single-cell sequencing to delineate MC3R-expressing neuronal subpopulations involved in developmental timing.
2. Gene therapy targeting hypothalamus-specific MC3R defects.
3. Exploration of MC3R agonists in treating cachexia and other chronic wasting disorders.

As a molecular bridge between nutritional status and developmental progression, precise modulation of MC3R offers a novel paradigm for treating growth and maturation disorders.